Biology subjects

Basturk, D.

Publications and source records attributed to Basturk, D..

2 recordsLinked to original sources

bioRxiv2025

Mapping the Peptide Interaction Fingerprint of the Behcet's disease associated HLA-B*51

The strongest genetic risk factor for Behcets disease, a relapsing inflammatory disorder marked by recurrent mucocutaneous ulcers and uveitis, is an allele of the class I major histocompatibility complex (MHC-I) molecule, which presents intracellular peptides to CD8+ T cells. The molecular mechanisms linking the peptide preferences of this allele (HLA-B*51:01) to dysregulated immunity remain unclear, limiting efforts to design peptide-based modulators of antigen presentation. Here, we define HLA-B*51:01s peptide selection rules by mapping the "interaction fingerprint" of 36 self-peptides using long-duration all-atom MD simulations. These uncovered a conserved hydrophobic-polar blueprint that is tuned by peptide length. High-speed atomic force microscopy rate in silico pulling experiments suggest a three-tier hierarchy of mechanical resilience: 9-mers resist the highest forces, 8-mers exhibit intermediate resistance, and 10/11-mers rupture most easily. Our comprehensive analysis provides an atomistic framework for understanding the molecular mechanisms underlying HLA-B*51:01 pathobiology and offers quantitative parameters to guide the design of therapeutic peptides or small molecules to modulate antigen presentation in Behcets disease. STATEMENT OF SIGNIFICANCEBehcets disease is strongly linked to HLA-B*51:01, a molecule that displays protein fragments to killer T cells, yet how this allele selects its peptides is poorly understood. Here, we combine all-atom equilibrium molecular dynamics simulations with steered MD pulling simulations that mimic high-speed atomic force microscopy experiments to map how 36 self-peptides of different lengths engage the HLA-B*51:01 groove. We uncover a conserved hydrophobic-polar interaction blueprint and show that 9-mers form the mechanically most resilient complexes, whereas shorter or longer peptides detach more easily under force. This length-tuned interaction "fingerprint" provides an atomistic framework for understanding HLA-B*51:01-driven immune dysregulation and guides the rational design of peptide-based or small-molecule modulators for Behcets disease.

biophysics↗

bioRxiv2025

Covariance-Based MD Simulation Analysis Pinpoints Nanobody Attraction and Repulsion Sites on SARS-CoV-2 Omicron Spike Protein

Mutations in the SARS-CoV-2 spike receptor-binding domain (RBD) of the Omicron variant enable broad escape from neutralizing antibodies (Abs) and nanobodies (Nbs), yet the atomistic basis of epitope-dependent loss of Nb binding remains unclear. We performed all-atom molecular dynamics (MD) simulations of 13 Nbs bound to the Omicron RBD to characterize their binding modes, binding-pose stability, and interfacial dynamics. Analysis of the trajectories and corresponding free-energy landscapes revealed that most Nbs occupied a single dominant basin but showed varying degrees of within-basin heterogeneity and often exhibited orientation shifts, whereas two Nbs (Nb21 and Sb14) showed pronounced pose plasticity and dissociated from the RBD. For the remaining 11 Nbs, covariance-matrix analysis mapped stabilizing and destabilizing residue couplings, revealing recurrent hydrophobic anchor patches within the receptor-binding motif and Nb-specific interaction patterns reflecting differences in the sequences and chemistries of their complementarity-determining regions. Omicron substitutions rewired interaction networks, shifted Nb binding orientations relative to the corresponding experimentally determined reference structures (obtained with the ancestral WT RBD for all Nbs except H3), and introduced unfavorable repulsion, either directly at mutation sites or indirectly via mutation-driven reorientation, thereby reducing interfacial stability. Low-speed steered MD unbinding simulations of the 11 Nb-RBD complexes and the ACE2-RBD complex, performed at a pulling velocity within the range used in high-speed AFM-based force spectroscopy, yielded lower mean unbinding work for all 11 Nbs than for ACE2. These simulations also revealed heterogeneous, stepwise Nb unbinding pathways in which receptor-binding ridge (RBR)-mediated anchoring maintained partial Nb attachment through newly formed interactions and stabilized transient intermediate binding poses. Together, these Nb-RBD interaction fingerprints and pathway-resolved unbinding simulations pinpoint epitope-specific determinants and mutation-induced clash sites, providing a mechanistic basis for diminished Nb binding.

biophysics↗